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| United States Patent |
5,030,630
|
|
Brantl
|
*
July 9, 1991
|
Use of 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine- for
treating diseases caused by reduced secretion of growth hormone
Abstract
The use of 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine and
pharmacological acid addition salts thereof for the release of growth
hormone.
| Inventors:
|
Brantl; Victor (Frauenplatz, DE)
|
| Assignee:
|
Boehringer Ingelheim KG (Ingelheim am Rhein, DE)
|
| [*] Notice: |
The portion of the term of this patent subsequent to July 25, 2006
has been disclaimed. |
| Appl. No.:
|
338690 |
| Filed:
|
April 17, 1989 |
Foreign Application Priority Data
| Current U.S. Class: |
514/215 |
| Intern'l Class: |
A61K 031/55 |
| Field of Search: |
514/215
|
References Cited
U.S. Patent Documents
| 3907996 | Sep., 1975 | Griss et al. | 514/215.
|
| 4400378 | Aug., 1983 | Innemee et al. | 514/215.
|
| 4851408 | Jul., 1989 | Brantl | 514/215.
|
Primary Examiner: Waddell; Frederick E.
Assistant Examiner: Henley, III; Raymond J.
Attorney, Agent or Firm: Frankhouser; D. E., Timbers; M-E. M., Stempel; A. R.
Parent Case Text
This is a division of application Ser. No. 130,909, filed Dec. 10, 1987,
now U.S. Pat. No. 4,851,408.
Claims
What is claimed is:
1. A method of treating disease in a warm-blooded animal caused by reduced
secretion of growth hormone which comprises administering to said animal a
growth-hormone-releasing amount of
6-allyl-2-amino-5,6,7,8-tetrahydro-4H-triazolo-[5,4-d]azepine or the
pharmacologically acceptable acid addition salts thereof.
Description
The invention relates to the use of a thiazoloazepine derivative and the
pharmacologically acceptable acid addition salts thereof for the release
of growth hormone, e.g. for treating growth disorders.
German Offenlegungsschrift No. 20 40 510 describes thiazolo-and
oxazolo-derivatives of general formula
##STR1##
wherein R.sub.1 represents a hydrogen atom, an alkyl group with 1 to 4
carbon atoms optionally substituted by a hydroxyl group, a benzoyl group
optionally substituted by a halogen atom or by a methyl or methoxy group,
or an allyl group and X represents an oxygen or sulphur atom, and the
physiologically acceptable acid addition salts thereof with inorganic or
organic acids.
It is also known from this Offenlegungsschrift that the compounds of
general formula I have valuable pharmacological properties; the
specification describes both antitussive and hypotensive properties,
depending on X. A delayed-release form for the oral treatment of
hypertension and angina pectoris is disclosed in DE-OS 28 36 387. U.S.
Pat. No. 4 400 378 also describes an anti-glaucoma property of compounds
of general formula I.
Moreover, 6-allyl-2-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine is
described in numerous scientific publications under the name B-HT 920.
Applications relating to a second medical indication were filed in the
form of DE-OS 35 02 365, relating to a composition for lowering the
prolactin serum level, and in DE-OS 35 03 963, concerning a composition
for the treatment of Parkinsonism. Compounds which bring about the release
of growth factor are already known from numerous publications and patent
applications (Bibl.: F. X. Coude et al., Trends in Biotechnology 1984,
Volume 2, page 83 ff; M. O. Thorner in "The Lancet", July 16, 1983, page
119 ff; EP-OS 0 136 475) These are polypeptides, generally with a sequence
of 40 amino acids. In the English-language publications, these peptides
are also referred to as "Growth Hormone Releasing Factor" (GRF). These
compounds may be prepared by conventional chemical synthesis or also by
genetic engineering. Owing to the complex structure of these peptides it
has hitherto not been possible to produce them in large quantities by
conventional synthesis and even genetic engineering does not produce them
any more cheaply on a larger scale.
Surprisingly, it has been found that B-HT 920 causes the release of growth
hormone in humans. BH-T 920 and the physiologically acceptable acid
addition salts thereof are suitable for preparing a drug for the treatment
of growth disorders. It may be used to treat diseases which are based on a
reduced secretion of growth hormone, e.g. growth disorders in children
such as restricted growth, and also in reduced metabolism, e.g.
malnutrition, cachexia caused by tumours or chemotherapy; chronic
anoxaemia caused by respiratory insufficiency or cardiopathy, kidney
failure. Other indications include bone fractures, burns, wound healing
and the acceleration of blood production.
For diagnostic purPoses, B-HT 920 can be used to stimulate the release of
growth hormone and thus determine whether there is sufficient growth
hormone in the hypophysis.
For the release of growth hormone, B-HT 920 and the acceptable acid
addition salts thereof (e.g. B-HT 920 Cl.sub.2) may be incorporated in the
conventional galenic preparations for oral, rectal, parenteral or
transdermal use.
The single dose by oral route for humans is normally between 0.05 mg and
0.3 mg, preferably 0.1 to 0.25 mg. When administered several times
throughout the day the total dosage may be between 0.6 and 1.0 mg.
The following are clinical trials investigating the release of growth
hormone by B-HT 920 Cl.sub.2.
The tests are carried out with six male subjects ranging in age from 21 to
46. Each subject was given 0.15 to 0.2 mg of B-HT 920 Cl.sub.2 in tablet
form.
The measurement of the growth hormone in the serum was carried out using a
standard radioimmunological process.
The serum levels were determined before and after administration. The blood
samples were taken through a fixed vein cannula which was put into
position 1 hour before administration of the substance and determination
of the 0 level. The measurements obtained are listed in Table I. They are
given in ng/ml.
______________________________________
Dosage Test 0 level Hours after medication
B-HT920C1.sub.2
subject t = 0 1 2 3 5 8
______________________________________
0.15 mg 1 0.3 0.5 0.3 3.5 4.4 0.4
0.15 mg 2 0.4 0.3 0.3 0.5 3.3 0.3
0.20 mg 3 1.5 0.4 2.5 9.5 1.0 0.5
0.15 mg 4 0.3 0.32 1.7 0.3 0.2 0.2
0.15 mg 5 0.3 7.3 0.6 0.4 0.2 0.3
0.15 mg 6 0.4 20.0 12.4 1.4 0.4 0.4
______________________________________
The substance is very well tolerated and no undesirable effects such as
dryness of the mouth, fatigue or dizziness are experienced.
The following Examples describe the preparation of some pharmaceutical
forms:
EXAMPLE I
Coated tablet core
______________________________________
Composition:
1 tablet core contains
______________________________________
B-HT 920 C1.sub.2 100 .mu.g
Lactose 38.45 mg
Corn starch 10.0 mg
Gelatine 1.0 mg
Magnesium stearate 0.5 mg
______________________________________
Method
The mixture of the active substance with lactose and corn starch is
granulated with a 10% aqueous gelatine solution by passing through a 1 mm
screen, dried at 40.degree. C. and passed through the same screen again.
The granules thus obtained are mixed with magnesium stearate and
compressed to form tablet cores. This procedure should be carried out in a
darkened room.
______________________________________
Weight of core: 50 mg
Punch: 5 mm, convex
______________________________________
The tablet core thus obtained are coated in known manner with a coating
consisting essentially of sugar and talc. The finished coated tablets are
polished with beeswax.
______________________________________
Weight of coated tablet:
100 mg
______________________________________
EXAMPLE II
Suppositories
______________________________________
1 suppository contains
______________________________________
B-HT 920 Cl.sub.2 100.0 .mu.g
Suppository mass (e.g. Witepsol W 45)
1690.0 mg
______________________________________
Method
The finely powdered substance is stirred, by means of an immersion
homogenizer, into the molten suppository mass which has been cooled to
40.degree. C. At 35.degree. C. the mass is poured into slightly chilled
moulds.
EXAMPLE III
Ampoules containing 200 mcg of B-HT 920
______________________________________
1 ampoule contains:
______________________________________
B-HT 920 200 .mu.g
Citric acid 7.0 mg
Sec. sodium phosphate 2H.sub.2 O
3.0 mg
Sodium phyrosulphite 1.0 mg
Distilled water ad 1.0 ml
______________________________________
Method
The buffer substances, active substance and sodium pyrosulphite are
dissolved successively in the distilled water which has been cooled under
a current of CO.sub.2. The solution is made up to the specified volume
with distilled water and filtered to remove any pyrogens.
Packaging: in brown ampoules under protective gas Sterilization: 20 minutes
at 120.degree. C.
The ampoule solution must be prepared and packaged in a darkened room.
EXAMPLE IV
Coated tablets containing 0.1 mg of B-HT 920 Cl.sub.2
______________________________________
1 tablet core contains:
______________________________________
B-HT 920 Cl.sub.2 100 .mu.g
Lactose 36.0 mg
Corn starch 12.4 mg
Gelatine 1.0 mg
Magnesium stearate 0.5 mg
______________________________________
Method
______________________________________
Analogously to Example I
______________________________________
Weight of core 50 mg
Punch: 5 mm, convex
Weight of coated tablet:
100 mg
______________________________________
EXAMPLE V
Gelatine capsules containing 250 mcg of B-HT 920 Cl.sub.2
______________________________________
1 capsule contains:
______________________________________
B-HT 920 Cl.sub.2 250 .mu.g
Corn starch 85.7 mg
______________________________________
Method
The substances are intensively mixed and packed into opaque capsules of
suitable size.
Example of preparation of a transdermal form
______________________________________
Composition:
______________________________________
9.744 g of Eudragit .RTM. E 30 D (Messrs. Rohm, Darmstadt)
0.600 g of Eudragit .RTM. E 100 (Messrs. Rohm, Darmstadt)
1.656 g of B-HT 920 Cl.sub.2
12.000 g
solids
6.000 g acetone
22.000 g
methanol
100.000 g
solution
______________________________________
The Eudragit.RTM. E 100 is previously dissolved in acetone, then the
Eudragit.RTM. E 30 D and half the methanol are added and the mixture is
stirred. When a homogeneous solution has been formed, the active substance
and the remaining methanol are added in batches. The resulting solution is
poured onto a film drawing apparatus (made by Erichsen) onto a PrePared
backing layer impervious to the active substance and spread with a doctor
blade at a position of 0.6 mm. After 10 minutes' drying a second and then
a third layer are applied with the doctor blade in the same position.
After drying, a film is obtained in a thickness of 100 microns. The film
is then packaged and, for use, is attached to the skin by means of a
suitable sticking plaster.
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